Opioid abuse is a common problem in the United States. It is estimated that 2.4 million people in this country use heroin at some time in their lives. Addiction to heroin has several long-term consequences, including molecular changes in the brain, hepatitis-risk taking behavior, HIV-risk taking behavior, and criminal behavior. Buprenorphine is a partial opioid agonist that has been commercially available since 1978 in sublingual form for outpatient treatment of opioid dependence. A transdermal patch is preferable to intramuscular or sublingual formulations for treatment of opioid dependence because it (a) increases patient compliance, (b) minimizes diversion of the buprenorphine for illicit use, (c) reduces the frequency of medical appointments, and (d) provides buprenorphine in a controlled manner, which minimizes fluctuations in blood concentration and limits withdrawal symptoms. However, conventional buprenorphine patches suffer from peak-and-trough variations in drug delivery. We hypothesize that two photon polymerization may be used to create fracture-resistant, biocompatible microneedle structures that can be used on a daily basis over several months for autonomous treatment of opioid addiction. An exploratory program is needed to assess the structural and functional properties of microneedle-based "smart" patches created using two photon polymerization. The proposed research plan contains four overlapping phases. Phase I will involve chemical characterization of Ormocer(R) materials created using two photon polymerization. Phase II will involve biological and functional characterization of Ormocer(R) microneedles. Phase III will involve integrating microneedles with pumping devices in autonomous "smart" patch devices. Phase IV will include a series of in vivo studies in mice to examine the predictive validity of the "smart" patch. The Phase IV experiments will build upon ongoing experiments within the co-PI's laboratory, which are examining the antinociceptive effects of opioid agonists as well as the development of tolerance and dependence following chronic opioid administration. The PI and the co-PI have already started developing preliminary studies;we have found that our complementary skills and facilities have allowed this joint research effort to progress at a much faster rate than would otherwise be possible. The proof-of-concept in vivo data from this award will form the basis for comprehensive in vivo animal and clinical studies that will examine the safety and efficacy of Ormocer(R) microneedles in a clinical environment. For example, comparison of "smart" patch against conventional patch, intramuscular injection, and other treatment modalities will be performed. We anticipate that an autonomous "smart" patch device could contribute to an improved quality of life, including improved social functioning, reduced HIV-risk taking behavior, reduced criminality, improved physical health, and improved psychological status, for patients seeking treatment for drug abuse. PUBLIC HEALTH RELEVANCE: In the proposed work, we will integrate microneedles with pumps in "smart" patches that may be used to provide autonomous management of opioid dependency and verification of compliance in a private setting. We envision several important public health outcomes from the proposed work. The data from this award will form the basis for in vivo animal and clinical studies that will examine the safety and efficacy of microneedle- based "smart" patches in a clinical environment. "Smart" patches may be used for active monitoring and treatment of patients undergoing maintenance withdrawal therapy;"phased" induction onto buprenorphine and other opioid addiction treatment agents;and management of pain resulting from cancer or other chronic conditions (e.g., neuropathic pain). Microneedles may also be integrated with multiple biosensors to provide autonomous blood sampling, analysis, calibration, and drug delivery for individualized treatment of patients with multiple chronic conditions (e.g., HIV positive status and opioid addiction). We anticipate that an autonomous "smart" patch device could contribute to an improved quality of life, including improved social functioning, reduced HIV-risk taking behavior, reduced criminality, improved physical health, and improved psychological status, for individuals seeking drug abuse treatment.